Loss of Hairless Confers Susceptibility to UVB-Induced Tumorigenesis via Disruption of NF-kappaB Signaling
Loss of Hairless Confers Susceptibility to UVB-Induced Tumorigenesis via Disruption of NF-kappaB Signaling
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DOI：
10.1371/journal.pone.0039691
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发表时间：
2012-06-25
期刊：
影响因子：
3.7
通讯作者：
Christiano, Angela M.
中科院分区：
文献类型：
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作者：
Kim, Hyunmi;Casta, Alexandre;Christiano, Angela M.
为了模拟鳞状细胞癌在体内的发展，研究人员长期以来一直倾向于无毛小鼠模型，如SKH-1小鼠，这些小鼠传统上被归类为“野生型”小鼠，而不考虑其无毛表型背后的遗传因素。这项工作表明，无毛(HR)基因突变不仅导致SKH-1和HR(-/-)小鼠的无毛表型，而且还导致核因子kappa B及其下游效应器的异常激活。我们发现，在表皮中，HR是一个早期的UVB反应基因，它调节核因子kappaB的激活，从而控制细胞对辐射的反应。因此，当HR突变动物的HR表达降低时，其核因子kappaB的活性也相应地增加，而UVB辐射则会增强这种活性。在HR突变的表皮中，NF-kappa B的这种结构性激活导致了大量下游效应因子的刺激，包括细胞周期调节因子细胞周期蛋白D1和细胞周期蛋白E、抗细胞凋亡蛋白Bcl2和促炎蛋白COX-2。因此，HR缺失会导致不受控制的表皮增殖状态，从而促进肿瘤的发展，而HR突变小鼠不应再被视为仅仅是无毛的野生型小鼠。相反，HR是一个关键的UVB反应基因，它的缺失创造了一个允许的环境，增强了肿瘤发生的增加。
In order to model squamous cell carcinoma development in vivo, researchers have long preferred hairless mouse models such as SKH-1 mice that have traditionally been classified as 'wild-type' mice irrespective of the genetic factors underlying their hairless phenotype. The work presented here shows that mutations in the Hairless (Hr) gene not only result in the hairless phenotype of the SKH-1 and Hr(-/-) mouse lines but also cause aberrant activation of NF kappa B and its downstream effectors. We show that in the epidermis, Hr is an early UVB response gene that regulates NF kappa B activation and thereby controls cellular responses to irradiation. Therefore, when Hr expression is decreased in Hr mutant animals there is a corresponding increase in NF kappa B activity that is augmented by UVB irradiation. This constitutive activation of NF kappa B in the Hr mutant epidermis leads to the stimulation a large variety of downstream effectors including the cell cycle regulators cyclin D1 and cyclin E, the anti-apoptosis protein Bcl-2, and the pro-inflammatory protein Cox-2. Therefore, Hr loss results in a state of uncontrolled epidermal proliferation that promotes tumor development, and Hr mutant mice should no longer be considered merely hairless 'wild-type' mice. Instead, Hr is a crucial UVB response gene and its loss creates a permissive environment that potentiates increased tumorigenesis.